The renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure. Angiotension II (AII), an octapeptide hormone is produced mainly in the blood during the cleavage of angiotension I by angiotension converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs, and is the end product of the RAS. AII is a powerful arterial vasoconstricter that exerts its action by interacting with specific receptors present on cell membranes. One of the possible modes of controlling the RAS is angiotension II receptor antagonism. Several peptide analogs of AII are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by their partial agonist activity and lack of oral absorption (M. Antonaccio. Clin. Exp. Hypertens. A4, 27-46 (1982); D. H. P. Streeten an H. Anderson, Jr. Handbook of Hypertension, Clinical Pharmacology of Antihypertensive Drugs, ed. A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984).
Recently, several non-peptide compounds have been described as AII antagonists. Illustrative of such compounds are those disclosed in U.S. Pat. Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847 and 4,880,804 in European Patent Applications 028,834; 245,637; 253,310; and 291,969; and in articles by A. T. Chiu, et al. (Eur. J. Pharm. Exp. Thetap, 157, 13-21 (1988)) and by P. C. Wong, At al. (J. Pharm. Exp. Therap, 247, 1-7(1988), Hypertension, 13, 489-497 (1989)). All of the U.S. Patents, European Patent Applications 028,834, 253,310, 399,731 and 400,974 and the two articles disclose substituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted phenyl.
Also, U.S. Patent Applications, Ser. Nos. 07/537,891 (filed June 18, 1990) and 07/665,389 (filed Mar. 6, 1991) disclose quinazolinones with substitution patterns different from those disclosed herein which are also Angiotensin II antagonists.